Co-administered low doses of ibuprofen and dexamethasone produce synergistic antinociceptive effects on neuropathic mechanical allodynia in rats

Abstract

Background: The traditional analgesics used to treat neuropathic pain such as anticonvulsants, opioids, and nonsteroidal anti-inflammatory drugs (NSAIDs) lack efficacy and/or carry unpleasant side effects. The present study aimed to investigate the synergistic antinociceptive effects of co-administered low doses of ibuprofen and dexamethasone in rats with trigeminal neuropathic pain. Materials and methods: A Sprague-Dawley rat model for trigeminal neuropathic pain was produced using mal-positioned dental implants. The left mandibular second molar was extracted under anesthesia and replaced with a miniature dental implant to induce injury to the inferior alveolar nerve. Results: Monotherapy with intraperitoneal injection of high-dose ibuprofen (30 mg/kg) or dexamethasone (10 mg/kg) but not low-dose ibuprofen (1, 5, 10 mg/kg) or dexamethasone (0.01, 1 mg/kg) attenuated the neuropathic mechanical allodynia in the rats with inferior alveolar nerve injury. We examined the synergistic antinociceptive effects of co-administered ibuprofen (5 mg/kg) and dexamethasone (0.01, 0.1, 1 mg/kg). The early co-administration of ibuprofen (5 mg/kg) with dexamethasone (0.1, 1 mg/kg) on postoperative days (POD) 1–3 significantly inhibited mechanical allodynia before the pain had been established. We also observed the synergistic antinociceptive effects of the same doses the combined treatment on mechanical allodynia on POD 7–9, when the pain had already been established. The attenuation of c-fos immuno-positive cells in the ipsilateral trigeminal subnucleus caudalis after the intraperitoneal co-administration of ibuprofen (5 mg/kg) with dexamethasone (1 mg/kg) confirmed these synergistic antinociceptive effects. Moreover, the magnitude of the effects of this co-administration was comparable with that of gabapentin both before and after the pain had been established. Conclusion: These results suggest that a combination of ibuprofen and dexamethasone at low doses is an alternative therapeutic strategy for neuropathic pain and provide a rationale for the use of such drug combinations in patients who are unable to tolerate high-dose monotherapy.